The purpose of this proposal is to bring together a group of investigators with a broad interest in interstitial lung disease, immunology, and cell and molecular biology and to investigate how immune and inflammatory events interrelate in the development of interstitial lung disease. Idiopathic pulmonary fibrosis (IPF) remains a disease of unknown etiology with a variable but in general poor prognosis. Our hypothesis is that IPF is a disorder of abnormal immunologic regulation in the lung. We view immunologic mechanisms from a broad perspective encompassing all inflammatory cells and mediators, including neutrophils, mast cells, and mononuclear phagocytes as well as lymphocytes. We will focus our research on the interactions between the immune and inflammatory system, specifically the macrophage and T lymphocyte, and parenchymal lung cells, specifically alveolar type II epithelial cells. We will investigate the regulation of inflammation, focusing on how it is perpetuated, what regulates the cessation of inflammation, and what links injury to fibrosis. Because we feel that understanding the early stages of interstitial lung disease is critical to providing insight into the pathogenesis, we have included two specific patient groups, progressive systemic sclerosis and berylliosis, which have subclinical as well as clinical pulmonary disease. Project of Dr. King is the main clinical project on IPF. This study will determine the value of non-invasive assessment of patients with interstitial lung disease including the importance of neutrophil and monocyte trafficking, the importance of macrophage phenotypes, and the role of proliferating type II cells in IPF. Project of Dr. Newman will investigate the pathogenesis of berylliosis with special emphasis on beryllium reactive subsets of T lymphocytes. Project of Dr. Doherty will study the fate of mononuclear phagocytes in interstitial lung disease. Project of Dr. Augustin will investigate the development of granuloma in mice with a specific emphasis on the role of subpopulations of T- lymphocytes. Project of Dr. Riches will determine the presence and regulation of specific macrophage phenotypes thought to be important in interstitial lung disease. Dr. Riches will study both macrophages from patients with interstitial lung disease and murine bone marrow derived macrophages whose function can be modulated in vitro. Project of Dr. Mason and Dr. Shannon will investigate the role of alveolar type II cells in interstitial lung disease.